Adjuvant Pembrolizumab/Chemo Misses Primary End Point of DFS in High-Risk Endometrial Cancer

Adjuvant treatment with pembrolizumab (Keytruda) plus chemotherapy with or without radiotherapy did not meet the prespecified primary end point of disease-free survival (DFS) compared with placebo plus adjuvant chemotherapy with or without radiotherapy in the phase 3 ENGOT-en11/GOG-3053/KEYNOTE-B21 study (NCT04634877) in patients with newly diagnosed, high-risk endometrial cancer after surgery with curative intent, according to data produced during a prespecified interim analysis conducted by an independent data monitoring committee.¹ The coprimary end point of the trial, overall survival (OS), was not formally evaluated, as superiority was not achieved for DFS.

Previously, the FDA granted priority review to the supplemental biologics license application for pembrolizumab plus chemotherapy for the treatment of patients with primary advanced or recurrent endometrial cancer based on phase 3 data from the NRG-GY018/KEYNOTE-868 trial and set a Prescription Drug User Fee Act target action date of June 21, 2024.

“While these results were not what we had hoped, we are focused on continuing to build on the established role of [pembrolizumab] in advanced endometrial carcinoma through our approved indications, while rapidly progressing clinical research evaluating [pembrolizumab]-based combinations and other investigational candidates, including antibody-drug conjugates, in endometrial and other types of gynecologic malignancies,” Gursel Aktan, MD, vice president of global clinical development at Merck Research Laboratories, stated in a press release.¹ “We would like to thank all the patients, the investigators, and our study collaborators for their participation in this trial.”

Endometrial carcinoma originates in the inner lining of the uterus and is the most prevalent uterine cancer type. Globally, it ranks as the sixth most common cancer among women and the 15th most common cancer overall. Despite the availability of primary treatment, there is a risk of recurrence in the form of distant metastasis, leading to poorer outcomes. Pembrolizumab is an anti-PD-1 therapy that boosts the body’s ability to identify and combat tumor cells. It is a humanized monoclonal antibody that disrupts the PD-1 interaction with its ligands, PD-L1 and PD-L2, stimulating T lymphocytes, which may impact both tumor and healthy cells.

Notably, pembrolizumab has 2 FDA-approved indications for patients with endometrial cancer. One indication is for advanced endometrial carcinoma that is mismatch repair–proficient or not microsatellite instability-high (MSI-H), in combination with lenvatinib (Lenvima), for patients with disease progression following prior systemic therapy who are not candidates for curative surgery or radiation. The second indication is as monotherapy in advanced endometrial carcinoma that is MSI-H or mismatch repair–deficient in patients with disease progression following prior systemic therapy who are not candidates for curative surgery or radiation.

Patients ages 18 years or older with a histologically confirmed new diagnosis of endometrial carcinoma or carcinosarcoma who had undergone curative-intent surgery and had an ECOG performance status of 0 or 1 were eligible to enroll onto the ENGOT-en11/GOG-3053/KEYNOTE-B21 trial. Patient eligibility criteria also included being at high risk of recurrence as assessed by the International Federation of Gynecology and Obstetrics (FIGO) staging criteria; being disease free with no evidence of locoregional disease or distant metastasis postoperatively; having no prior radiation or systemic therapy; and having adequate organ function.²

Patients with a uterine mesenchymal tumor; surgical stage I/II endometrial cancer without known aberrant p53 expression or p53 mutation; a known POLE mutation; or FIGO stage IVB disease of any histology were not eligible for enrollment. Patients were also ineligible if they had residual tumors post-surgery; a history of a second malignancy; or prior therapy with an anti-PD-L1 or anti-PD-L2 agent.

Additional exclusion criteria include a diagnosis of immunodeficiency or receipt of chronic systemic steroid therapy; exposure to any immunosuppressive therapy within 7 days before the first study dose; severe hypersensitivity to pembrolizumab; active autoimmune disease necessitating systemic treatment in the past 2 years; history of noninfectious pneumonitis or active pneumonitis; allogeneic tissue or solid organ transplant; or inadequate recovery or complications from prior surgery.²

The trial enrolled an estimated 1095 patients who were randomly assigned to receive pembrolizumab at 200 mg every 3 weeks for 6 cycles plus concurrent standard-of-care chemotherapy for 4 or 6 cycles, followed by pembrolizumab at 400 mg every 6 weeks for an additional 6 cycles with or without radiotherapy; or placebo every 3 weeks for 6 cycles plus concurrent SOC chemotherapy for 4 or 6 cycles, followed by placebo every 6 weeks for an additional 6 cycles with or without radiotherapy.¹

Notably, the primary end points for ENGOT-en11/GOG-3053/KEYNOTE-B21 included DFS and OS; safety was a key secondary end point.

The safety profile of pembrolizumab remained consistent with what has been previously observed with the agent in other clinical trials, and no new safety signals were identified.

Merck will work with investigators to share the results of the trial with the scientific community; a full evaluation of the ENGOT-en11/GOG-3053/KEYNOTE-B21 data is ongoing.¹

References

1. Merck provides update on phase 3 KEYNOTE-B21 trial evaluating Keytruda (pembrolizumab) plus chemotherapy, with or without radiotherapy, for patients with newly diagnosed, high-risk endometrial cancer after surgery with curative intent. News Release. Merck. May 9, 2024. Accessed May 9, 2024. https://www.merck.com/news/merck-provides-update-on-phase-3-keynote-b21-trial-evaluating-keytruda-pembrolizumab-plus-chemotherapy-with-or-without-radiotherapy-for-patients-with-newly-diagnosed-high-risk-endometrial-c/
2. Study of pembrolizumab (MK-3475) in combination with adjuvant chemotherapy with or without radiotherapy in participants with newly diagnosed endometrial cancer after surgery with curative intent (MK-3475-B21 / KEYNOTE-B21 / ENGOT-en11 / GOG-3053). ClinicalTrials.gov. Updated November 21, 2023. Accessed May 9, 2024. https://clinicaltrials.gov/study/NCT04634877